Journal ofNeuro-Oncologyl3: 165-171, 1992. ©1992KluwerAcademic Publishers. Printed in theNetherlands.
Clinical Study
Neurotropic melanoma A case report and review o f the literature Ellen E. Mack, 1 and Edward C. Gomez 2
1Department of Neurology, Cornell University Medical Center and Memorial Sloan-Kettering Cancer Center, New York, NY," 2Department of Dermatology, UC, Davis School of Medicine, USA
Key words: melanoma, neurotropic, neurotropism, cranial neuropathy Abstract Neurotropic melanoma is a rare tumor with a biphasic growth pattern associated with a change in morphology from melanocytic features toward Schwann cell features. The tumor thereby develops a capacity for infiltrating nerves which may result in clinically evident cranial neuropathies, most commonly of the fifth and seventh cranial nerves. The histology of this lesion is difficult to interpret; it often erroneously appears fibrous in origin and may be considered to be benign. Despite this benign appearance histologically, the tumor behaves aggressively with multiple local recurrences and possible CNS invasion by either direct perineural growth or distant metastases. We review the literature of neurotropic melanomas and report a 46th case which describes a typical course with neural invasion. Although a rare cause of cranial neuropathies, the neurologist should consider this entity in the differential diagnosis and the history of a recurrent skin lesion of the face should be sought whenever examining such a patient.
Neurotropic melanoma (NTM) is a rare and unusual cause of cranial neuropathies. The perineural spread of head and neck cancers resulting in cranial neuropathies and central nervous system invasion has been previously well described [1]. Of these tumors, some originate in the skin and are usually squamous cell carcinomas [2]. Rarer causes of perineural spread of cutaneous tumors include adenoid cystic carcinoma, basal cell carcinoma, keratoacanthoma, congenital melanocytic nevus, Spitz's nevus, and neurotropic melanoma [3]. The latter is an uncommonly reported tumor first described by Reed and Leonard [4] in 1979. It is a tumor with a biphasic pattern of growth, initially presenting as a mildly abnormal growth of melanocytes, which was called melanocytic dysplasia by Reed (this is a disputed term - see below). The tumor eventually recurs as a more obviously malignant lesion with a change in cell morphology and tissue behaviour.
During this latter phase the tumor takes on the property of neurotropism, resulting in direct neural invasion and clinically evident cranial neuropathies. The following case exemplifies a typical course.
Case report A 59 year old gentleman presented with cranial neuropathies after a 9 year history of a recurrent lip lesion. He initially sought medical attention for a persistent ulcerated lesion of the right lower lip, which upon resection then and again 2 years later was interpreted as benign. Soon after the second resection, he developed a painless mass in the right submandibular area. Resection done at his local hospital was interpreted as a malignant fibrous histiocytoma. The patient was referred to a major medical center, where the pathology of malignant
166
Fig. 1. Sections of skin. (a) Low power view, showing the presence of nests of atypical melanocytes with large nuclei within the
epidermis, extending from the basal layer to the stratum corneum (right side of section). Scattered throughout the dermis are cords and nests of atypical melanocytes, which invade neurovascular structures in the lower reticular dermis, (b) High power view of nerves at the junction of the reticular dermis and subcutaneous fat, showing invasion and replacement of nerves by melanocytes with spindle cell morphology and large, atypical nuclei. Note the preservation of the architecture of the nerve bundles. fibrous histiocytoma was confirmed, although a squamous cell carcinoma or m e l a n o m a could not be excluded. At this time, the patient had an essentially normal general and neurologic exam. His lip lesion was well healed without evidence of tumor recurrence. H e was noted to have actinic lesions of the face and u p p e r extremities, including multiple actinic keratoses and a basal cell carcinoma. The patient was fair in complexion and admitted to a history of considerable sun exposure. H e then underwent a right radical neck dissection for treatment of the presumed histiocytoma; no residual
tumor was found. Post-operatively, he received 8 courses of Adriamycin, Cytoxan and Vincristine. Four years later, the patient complained of a tightness of his right lower lip. On examination, a firm indurated mass with overlying anaesthesia was noted at the site of the original lip lesion. A punch biopsy was reported as benign, but a repeat biopsy showed atypical spindle shaped cells deep within the dermis with nests of atypical melanocytes extending up through the epidermis (Fig. la). Tissue stains were positive for S-100 and Vimentin and negative for keratins and desmin, consistent with a diagnosis of melanoma. A wider excision including resection of the lip and mandible, confirmed the
167 diagnosis and, although the tissue margins were free, tumor was noted to be infiltrating along subcutaneous nerves (Fig. lb) to the alveolar nerve. Post-operatively 2400 Rads of radiation were delivered by high dose fractionation to the base of the skull, with special attention to the foramen ovale. Approximately a year after completion of this treatment, the patient began to note both progressive numbness and paralysis of the entire right side of his face. A C T scan of the head taken showed both extra- and intracranial tumor with infiltration of the muscles of mastication and parotid gland, and extension of the tumor along the course of the fifth cranial nerve through the foramen ovale, towards the cavernous sinus and brainstem (Fig. 2). Examination showed complete loss of sensation to all modalities in the entire distribution of the right trigeminal nerve. The motor division was difficult to assess secondary to extensive facial surgery. There was a dense right sided facial paralysis, including the frontalis muscle; taste was intact. Corneal reflexes were absent on the right with no consenual response on the left. Extraocular movements were full and conjugate but there was excessive tearing of the right eye. The remainder of the neurologic examination was normal.
Discussion
Of the 46 cases of N T M described in the literature [3-14], 36 occurred in the head and neck, including 21 of the face, 7 of the lip, 5 of the neck and 3 of the ear (Table 1). The remaining 10 were of the trunk and extremities including a single description of a NTM of the vulva. This predilection for the head and neck is consistent with the distribution of other actinically related malignancies as well as the high density of cutaneous nerves found in the face. Most commonly the trigeminal and facial nerves were involved, as expected based on their rich cutaneous innervation and close inter-relationship. Men represented 60% of cases and the mean age of onset of NTM was approximately 60 years, but varied from 28 to 86 years. In more than 50% of cases, there was a history of an initial pigmented lesion, usually a lentigo maligna. In many cases, however, it was
Fig. 2. Computerized tomography. (a) Axial CT scan showing extension of tumor along the course of the right trigeminal nerve to the brain stem, with mild compression of the latter. (b) Coronal CT scan showing bony destruction at the base of the skull, with involvement of the right cavernous sinus.
felt that the primary lesion may have been destroyed at the time of surgery, as these precursor lesions are often small, easily missed, and in some instances have been present as long as 17 years [14].
168 Table 1.
Author
Age/sex
Location
Duration (site) Alive disease free
Ackerman [3]
Warner [7]
65M 82F 49F 28F 51M 74F 67M 67M 65F 68F 58F 79F 51M 80F 52M 57F 29M 84M 50M 37M 37M 83M 62M 73M 61M 53F 76F 38M 73M 58F 82M 86F 61M 76M 60M 35M 70F
Warner [8] Warner [9] Warner [10] Khalil [11]
51F 44M 60F 46M
DiMaio [12] Woodruff [13] McGinnis [14] Mack Totals
64M 37F 32M 59M 60%M, 40%F
Reed [4]
Kossard [5]
Gentile [6]
Forehead Nose Cheek Arm Ear Arm Cheek Temple Arm Nose Chin Neck Ear Temple Face Neck Lip Temple Neck Lip Forehead Lip Lip Chest Neck Arm Cheek Chest Back Neck Shoulder Cheek Arm Ear Cheek Chin Chin Face Vulva Lip Face Temple Temple Cheek Lip Lip
Alive with disease
Deceased with disease
2.5yr 6yr 12yr 9yr (CNS, Chest) 3yr 3yr 2yr 3yr 6.5yr 1.3 yr 28 mo 2yr 3 yr (CNS) 2 yr (CNS) 2yr (Bone) 4yr 3 yr (CNS) 1.7yr 2yr unknown I yr 19too unknown 6mo 19too 42 mo 14mo 9mo 4yr 15mo 9mo 10 mo 9too 7 yr (CN5, 6, 7) 2 yr (CN5) (Lung) 23 mo (Lung) 5 yr (CN5) 10yr (CNS, Lung, Rib, CN7, ?CN3) 1.1 yr CN6, ?CN2 2yr 16/40 (40%)
9 yr (CN5, 7) 12/40 (30%)
12/40 (30%)
169 Recurrences were frequent and occurred from 5 months to 6 years after presentation. While the initial lesions were melanotic, the recurrences were often amelanotic. The recurrent tumor tends to invade local structures, but distant metastases have been found in lymph nodes, lung, pancreas, bone and the CNS [4]. More common than the tendency for metastasis, however, and of greater interest to neurologists, is the tendency for this tumor to spread along neural structures due to neurotropism. On microscopic examination of the tumor, one can typically see invasion of tumor cells into the endoneurial space of small cutaneous nerves and even replacement of entire nerves, the distinguishing characteristic of NTM. Futhermore, neural invasion can advance to the point where larger nerves are involved and the patient develops clinical evidence of a cranial neuropathy. This is well exemplified in cases described in the literature. Warner [10] presented a case of a woman with progressive painful parathesias of the face diagnosed as trigeminal neuralgia of the maxillary nerve. She had a concomitant pigmented lesion of the face that had a benign histology on multiple biopsies. The trigeminal neuralgia was unresponsive to carbamazepine and local nerve block. She later developed intermittent diplopia secondary to a ipsilateral 6th nerve palsy, as well as eventual hypesthesia of the entire involved side of the face. A C T scan showed a maxillary sinus mass extending into the cavernous sinus. Upon resection, the maxillary nerve was noted to be thickened and the foramen rotundum was enlarged to 2 to 3 times its normal diameter. The diagnosis of NTM was then made upon tissue examination. A similar case described by Khalil [11] is of a patient with a cutaneous lesion of the right temple which eventually invaded the orbit by neural extension as well as invading the seventh nerve producing a facial paralysis. The tumor was resected and the pathology was consistent with a NTM. The patient later went on to develop distant intraparenchymal CNS metastases. A third case, described by Gentile [6], is of a male with a pigmented lesion of the right face who went on to develop a right 5th, 6th, and 7th nerve
palsy, including both motor and sensory divisions of the trigeminal nerve. CT and MRI scans did not demonstrate the neural involvement and CSF studies were normal.
H&topathology Melanomas develop largely from melanocytes in the basal layer of the epidermis, where they proliferate for a variable period, spreading laterally. The tumor eventually grows downward through the dermis, infiltrating the vascular and neural structures within the reticular dermis, and demonstrating the capacity for distant spread. Some melanomas grow downward without significant cellular atypism and show mild tissue changes. Such lesions were termed 'minimal deviation melanomas' by Reed and Leonard [15], who felt them to be a precursor lesion of NTM. In their paper, many of the original lesions were felt to be recognizable as a lentigo maligna (Hutchinson's freckle), a slowly expanding melanocytic lesion, which eventually invades to become a frank melanoma. Others, particularly Ackerman [16], have disagreed with this and feel strongly that the term 'minimal deviation melanoma' is a flawed concept that need not be invoked to describe the melanomas that lack significant cellular atypism and tissue changes, and that the term 'dysplasia' is a useless term that should be discarded. Dubow and Ackerman [17] also holds that lentigo maligna-type lesions are, from the outset, slowly growing melanomas, rather than premalignant lesions. Therefore, they regards the term, 'lentigo maligna' as inappropriate and use the term melanoma in situ. In NTM, melanocytes with a spindle cell morphology often cease melanogenesis, develop neuroid properties, such as fasicle formation or neurotropism, and invade cutaneous nerves in preference to vascular spread. Because of their spindle cell morphology and neuroid features, they are initially confused with benign lesions, are later thought to be spindle cell squamous carcinomas or malignant fibrous histiocytomas, and are eventually recognized as NTM. The usual clinical evolution of a NTM consists of
170
Fig. 3. C u t a n e o u s nerves in various stages of replacement by tumor cells. (a) Two nerves in the subcutaneous fat. Note the early invasion of the right side of the lower nerve. (b) More extensive replacement of a nerve by t u m o r cells which compress the few remaining normal cells. (c) Massive replacement of a larger nerve by tumor. Note that t u m o r cells are contained within the connective tissue sheath and preserve the architecture of the surrounding tissue.
a melanocytic lesion, which is treated but recurs as one or more flesh-colored papules or nodules. Microscopically, the tumor exhibits fascicles of spindle cells with pale cytoplasms and oval nuclei. Initially, the tumor cells tend to show minimal atypism, although there is some variation in the size and shape of nuclei. The fascicles invade the dermis and are encased by sheaths that resemble a perineurium. These fasicles can be shown to blend with the perineurium of cutaneous nerves and one can often demonstrate atypical cells infiltrating the endoneurial space and, eventually, entirely replacing the nerve while maintaining the overall neuronal architecture, without involvment of adjacent tissue (Fig. 3). One sees broadened hypercellular nerves consisting of tumor cells intermixed with normal Schwann cells. Reed and Leonard [4], feel that the neuroid properties of NTM are indicative of a Schwann cell differentiation of the melanocytes, which, having lost their melanogenic role, instead begin to grow in fasicular formation and to invade nerves, based on their common neural crest origin with Schwann cells [18]. The morphologic interpretation of Schwann cell features has been supported by ultrastructural studies of neurotropic melanomas by two separate groups [9, 12]. DiMaio [12] described long cell processes arranged in bundles and closely apposed cell membranes with infoldings suggestive of Schwann cell neoplasms. Warner [9] described concentric laminations surrounding membrane bound cytoplasm that were interpreted as attempts at myelin formation. Due to the lack of melanogenesis and the often benign or low grade appearance of the lesion, diagnosis of NTM can often be difficult, especially early in the evolution of the tumor. Early NTM's are frequently misread as a neurofibroma, a bleu nevus or even as reactive fibroplasia [19]. Later, recurrences are difficult to differentiate from a spindle cell squamous carcinoma or a malignant fibrous histiocytoma, as seen in the case presented. Immunohistochemical stains have been shown to be useful in differentiating some of these entities [5, 11]. The S-100 protein, originally described in astrocytes and oligodendrocytes, has also been shown to be present in Schwann cells, melanocytes and even Langerhans cells [5, 10]. Therefore, NTM and the
171 full s p e c t r u m o f m e l a n o c y t i c n e o p l a s m s f r o m c o m m o n nevi to m a l i g n a n t m e l a n o m a s stain for S-IO0, b u t s p i n d l e cell t u m o r s of c a r c i n o m a t o u s o r fibroblastic origin, which a r e so difficult to d i f f e r e n t i a t e f r o m N T M , d o n o t so stain. It has also b e e n p r o p o s e d that S-IO0 staining m a y b e h e l p f u l in d e t e r m i n i n g w h e t h e r surgical tissue m a r g i n s a r e a d e quate.
3.
4.
5.
6.
Treatment and prognosis 7. T o d a t e , t r e a t m e n t has b e e n p r i m a r i l y surgical, b u t d i s e a s e c o n t r o l has b e e n p o o r d u e to t h e t e n d e n c y o f t h e t u m o r to h a v e infiltrating m a r g i n s a n d to i n v a d e a l o n g n e r v e s . R a d i a t i o n t h e r a p y has b e e n u s e d as an a d j u n c t [6], b u t no c l e a r b e n e f i t has b e e n d e m o n s t r a t e d . C h e m o t h e r a p y has also b e e n att e m p t e d , i n c l u d i n g i n t r a - a r t e r i a l cisplatin [6] a n d d o x o r u b i c i n [9], b u t d a t a a r e insufficient for extrap o l a t i o n , O u t c o m e is difficult to assess d u e to a p a u c i t y o f cases a n d i n c o m p l e t e f o l l o w - u p , b u t app r o x i m a t e l y 3 0 % o f p a t i e n t s h a d d i e d with active d i s e a s e , 30% w e r e alive with active d i s e a s e , a n d 40% a p p e a r e d free o f d i s e a s e , at the t i m e t h e cases w e r e p u b l i s h e d . P e r h a p s , use o f S-100 staining of surgical s p e c i m e n s to d e t e r m i n e m a r g i n s will l e a d to m o r e c o m p l e t e r e s e c t i o n s a n d b e t t e r survival.
8. 9.
10.
11.
12.
13.
14.
Acknowledgements
15.
T h e a u t h o r s wish to t h a n k D r . H e r b e r t O e t t g e n for p r o v i d i n g t h e clinical m a t e r i a l a n d r a d i o g r a p h s , D r . J a m e s W o o d r u f f for p r o v i d i n g p h o t o m i c r o g r a p h s o f t h e case r e p o r t e d , a n d Dr. J e r o m e Posner for r e v i e w i n g t h e m a n u s c r i p t a n d m a k i n g m a n y helpful suggestions.
16.
References
19.
1. Ballantyne A J, McCarten AB, Ibanez MJ: The extension of cancer of the head and neck through peripheral nerves. Am J Surg 106: 651-666, 1963 2. Clouston PD, Sharpe DM~ Corben A J, Kos S, Kennedy PJ: Perineural spread of cutaneous head and neck cancer: its
17.
18.
orbital and central neurologic complications. Arch Neurol 47: 73-77, 1990 Ackerman AB, Godomski J: Neurotropic malignant melanoma and other neurotropic neoplasms in the skin. Am J Dermatopathol 6 (Suppl 1): 63-80, 1984 Reed RJ, Leonard DD: Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg Pathol 3: 301-311, 1979 Kossard S, Doherty E, Murray E: Neurotropic melanoma: a variant of desmoplastic melanoma. Arch Dermatol 123: 907-912, 1987 Gentile RD, Donovan DT: Neurotropic melanoma of the head and neck. Laryngoscope 95: 1161-1166, 1985 Warner TF, Lloyd RV, Hafez GR, Angevine JM: Immunocytocbemistry of neurotropic melanoma. Cancer 53: 254257, 1984 Warner TF, Hafez GR, Buchler DA: Neurotropic melanoma of the vulva. Cancer 49: 999-1004, 1982 Warner TF, Hafez GR, Finch RE, Brandenberg JH: Schwann cell features in neurotropic melanoma. J Cutan Pathol 8: 177-187, 1981 Warner TF, Ford CN, Hafez GR: Neurotropic melanoma of the face invading the maxillary nerve. J Cutan Patho112: 520-527, 1985 Khalil MK, Duguid WP: Neurotropic malignant melanoma of right temple with orbital metastasis: a clinicopathological case report. Brit J Ophthalmol 71: 41-46, 1987 DiMaio SM, Mackay B, Smith JL, Dickersin GR: Neurosarcomatous transformation in malignant melanoma: an ultrastructural study. Cancer 50: 2345-2354, 1982 Woodruff WW, Yeates AE, McLendon RE: Perineural tumor extension to the cavernous sinus from superficial facial carcinoma: CT manifestations. Radiol 161: 395-399, 1986 McGinnis JP, Greet JL, Wolfe NL: Neu~otropic melanoma of the lower lip. J Oral Pathol 15: 445-449, 1986 Reed RJ: A classification of melanocytic dysplasias and malignant melanomas. Am J Dermatopathol 6 (Suppl 1): 195-206, 1984 Ackerman AB: What Naevus is dysplastic, a syndrome and the commonest precursor of malignant melanoma? A riddle and an answer. Histopathology 13: 241-256, 1988 Dubow BE, Ackerman AB: Malignant Melanoma in Situ: the evolution of a concept. Modern Pathology 13: 734-744, 1990 Weston JA: The migration and differentiation of neural crest cells. Advances in Morphogenesis 8: 41-114, 1971 Kibbi A, Mihm MC: Malignant melanoma with desmoplasia and neurotropism. J Dermatol Surg Oncol 13: 12041208, 1987
Address for offprints: E.E. Mack, Department of Neurosurgery, Division of Neurooncology, University of California at San Francisco, ACC Building, Rm A841, San Francisco, CA 94143-0372, USA
Clinical Study
Neurotropic melanoma A case report and review o f the literature Ellen E. Mack, 1 and Edward C. Gomez 2
1Department of Neurology, Cornell University Medical Center and Memorial Sloan-Kettering Cancer Center, New York, NY," 2Department of Dermatology, UC, Davis School of Medicine, USA
Key words: melanoma, neurotropic, neurotropism, cranial neuropathy Abstract Neurotropic melanoma is a rare tumor with a biphasic growth pattern associated with a change in morphology from melanocytic features toward Schwann cell features. The tumor thereby develops a capacity for infiltrating nerves which may result in clinically evident cranial neuropathies, most commonly of the fifth and seventh cranial nerves. The histology of this lesion is difficult to interpret; it often erroneously appears fibrous in origin and may be considered to be benign. Despite this benign appearance histologically, the tumor behaves aggressively with multiple local recurrences and possible CNS invasion by either direct perineural growth or distant metastases. We review the literature of neurotropic melanomas and report a 46th case which describes a typical course with neural invasion. Although a rare cause of cranial neuropathies, the neurologist should consider this entity in the differential diagnosis and the history of a recurrent skin lesion of the face should be sought whenever examining such a patient.
Neurotropic melanoma (NTM) is a rare and unusual cause of cranial neuropathies. The perineural spread of head and neck cancers resulting in cranial neuropathies and central nervous system invasion has been previously well described [1]. Of these tumors, some originate in the skin and are usually squamous cell carcinomas [2]. Rarer causes of perineural spread of cutaneous tumors include adenoid cystic carcinoma, basal cell carcinoma, keratoacanthoma, congenital melanocytic nevus, Spitz's nevus, and neurotropic melanoma [3]. The latter is an uncommonly reported tumor first described by Reed and Leonard [4] in 1979. It is a tumor with a biphasic pattern of growth, initially presenting as a mildly abnormal growth of melanocytes, which was called melanocytic dysplasia by Reed (this is a disputed term - see below). The tumor eventually recurs as a more obviously malignant lesion with a change in cell morphology and tissue behaviour.
During this latter phase the tumor takes on the property of neurotropism, resulting in direct neural invasion and clinically evident cranial neuropathies. The following case exemplifies a typical course.
Case report A 59 year old gentleman presented with cranial neuropathies after a 9 year history of a recurrent lip lesion. He initially sought medical attention for a persistent ulcerated lesion of the right lower lip, which upon resection then and again 2 years later was interpreted as benign. Soon after the second resection, he developed a painless mass in the right submandibular area. Resection done at his local hospital was interpreted as a malignant fibrous histiocytoma. The patient was referred to a major medical center, where the pathology of malignant
166
Fig. 1. Sections of skin. (a) Low power view, showing the presence of nests of atypical melanocytes with large nuclei within the
epidermis, extending from the basal layer to the stratum corneum (right side of section). Scattered throughout the dermis are cords and nests of atypical melanocytes, which invade neurovascular structures in the lower reticular dermis, (b) High power view of nerves at the junction of the reticular dermis and subcutaneous fat, showing invasion and replacement of nerves by melanocytes with spindle cell morphology and large, atypical nuclei. Note the preservation of the architecture of the nerve bundles. fibrous histiocytoma was confirmed, although a squamous cell carcinoma or m e l a n o m a could not be excluded. At this time, the patient had an essentially normal general and neurologic exam. His lip lesion was well healed without evidence of tumor recurrence. H e was noted to have actinic lesions of the face and u p p e r extremities, including multiple actinic keratoses and a basal cell carcinoma. The patient was fair in complexion and admitted to a history of considerable sun exposure. H e then underwent a right radical neck dissection for treatment of the presumed histiocytoma; no residual
tumor was found. Post-operatively, he received 8 courses of Adriamycin, Cytoxan and Vincristine. Four years later, the patient complained of a tightness of his right lower lip. On examination, a firm indurated mass with overlying anaesthesia was noted at the site of the original lip lesion. A punch biopsy was reported as benign, but a repeat biopsy showed atypical spindle shaped cells deep within the dermis with nests of atypical melanocytes extending up through the epidermis (Fig. la). Tissue stains were positive for S-100 and Vimentin and negative for keratins and desmin, consistent with a diagnosis of melanoma. A wider excision including resection of the lip and mandible, confirmed the
167 diagnosis and, although the tissue margins were free, tumor was noted to be infiltrating along subcutaneous nerves (Fig. lb) to the alveolar nerve. Post-operatively 2400 Rads of radiation were delivered by high dose fractionation to the base of the skull, with special attention to the foramen ovale. Approximately a year after completion of this treatment, the patient began to note both progressive numbness and paralysis of the entire right side of his face. A C T scan of the head taken showed both extra- and intracranial tumor with infiltration of the muscles of mastication and parotid gland, and extension of the tumor along the course of the fifth cranial nerve through the foramen ovale, towards the cavernous sinus and brainstem (Fig. 2). Examination showed complete loss of sensation to all modalities in the entire distribution of the right trigeminal nerve. The motor division was difficult to assess secondary to extensive facial surgery. There was a dense right sided facial paralysis, including the frontalis muscle; taste was intact. Corneal reflexes were absent on the right with no consenual response on the left. Extraocular movements were full and conjugate but there was excessive tearing of the right eye. The remainder of the neurologic examination was normal.
Discussion
Of the 46 cases of N T M described in the literature [3-14], 36 occurred in the head and neck, including 21 of the face, 7 of the lip, 5 of the neck and 3 of the ear (Table 1). The remaining 10 were of the trunk and extremities including a single description of a NTM of the vulva. This predilection for the head and neck is consistent with the distribution of other actinically related malignancies as well as the high density of cutaneous nerves found in the face. Most commonly the trigeminal and facial nerves were involved, as expected based on their rich cutaneous innervation and close inter-relationship. Men represented 60% of cases and the mean age of onset of NTM was approximately 60 years, but varied from 28 to 86 years. In more than 50% of cases, there was a history of an initial pigmented lesion, usually a lentigo maligna. In many cases, however, it was
Fig. 2. Computerized tomography. (a) Axial CT scan showing extension of tumor along the course of the right trigeminal nerve to the brain stem, with mild compression of the latter. (b) Coronal CT scan showing bony destruction at the base of the skull, with involvement of the right cavernous sinus.
felt that the primary lesion may have been destroyed at the time of surgery, as these precursor lesions are often small, easily missed, and in some instances have been present as long as 17 years [14].
168 Table 1.
Author
Age/sex
Location
Duration (site) Alive disease free
Ackerman [3]
Warner [7]
65M 82F 49F 28F 51M 74F 67M 67M 65F 68F 58F 79F 51M 80F 52M 57F 29M 84M 50M 37M 37M 83M 62M 73M 61M 53F 76F 38M 73M 58F 82M 86F 61M 76M 60M 35M 70F
Warner [8] Warner [9] Warner [10] Khalil [11]
51F 44M 60F 46M
DiMaio [12] Woodruff [13] McGinnis [14] Mack Totals
64M 37F 32M 59M 60%M, 40%F
Reed [4]
Kossard [5]
Gentile [6]
Forehead Nose Cheek Arm Ear Arm Cheek Temple Arm Nose Chin Neck Ear Temple Face Neck Lip Temple Neck Lip Forehead Lip Lip Chest Neck Arm Cheek Chest Back Neck Shoulder Cheek Arm Ear Cheek Chin Chin Face Vulva Lip Face Temple Temple Cheek Lip Lip
Alive with disease
Deceased with disease
2.5yr 6yr 12yr 9yr (CNS, Chest) 3yr 3yr 2yr 3yr 6.5yr 1.3 yr 28 mo 2yr 3 yr (CNS) 2 yr (CNS) 2yr (Bone) 4yr 3 yr (CNS) 1.7yr 2yr unknown I yr 19too unknown 6mo 19too 42 mo 14mo 9mo 4yr 15mo 9mo 10 mo 9too 7 yr (CN5, 6, 7) 2 yr (CN5) (Lung) 23 mo (Lung) 5 yr (CN5) 10yr (CNS, Lung, Rib, CN7, ?CN3) 1.1 yr CN6, ?CN2 2yr 16/40 (40%)
9 yr (CN5, 7) 12/40 (30%)
12/40 (30%)
169 Recurrences were frequent and occurred from 5 months to 6 years after presentation. While the initial lesions were melanotic, the recurrences were often amelanotic. The recurrent tumor tends to invade local structures, but distant metastases have been found in lymph nodes, lung, pancreas, bone and the CNS [4]. More common than the tendency for metastasis, however, and of greater interest to neurologists, is the tendency for this tumor to spread along neural structures due to neurotropism. On microscopic examination of the tumor, one can typically see invasion of tumor cells into the endoneurial space of small cutaneous nerves and even replacement of entire nerves, the distinguishing characteristic of NTM. Futhermore, neural invasion can advance to the point where larger nerves are involved and the patient develops clinical evidence of a cranial neuropathy. This is well exemplified in cases described in the literature. Warner [10] presented a case of a woman with progressive painful parathesias of the face diagnosed as trigeminal neuralgia of the maxillary nerve. She had a concomitant pigmented lesion of the face that had a benign histology on multiple biopsies. The trigeminal neuralgia was unresponsive to carbamazepine and local nerve block. She later developed intermittent diplopia secondary to a ipsilateral 6th nerve palsy, as well as eventual hypesthesia of the entire involved side of the face. A C T scan showed a maxillary sinus mass extending into the cavernous sinus. Upon resection, the maxillary nerve was noted to be thickened and the foramen rotundum was enlarged to 2 to 3 times its normal diameter. The diagnosis of NTM was then made upon tissue examination. A similar case described by Khalil [11] is of a patient with a cutaneous lesion of the right temple which eventually invaded the orbit by neural extension as well as invading the seventh nerve producing a facial paralysis. The tumor was resected and the pathology was consistent with a NTM. The patient later went on to develop distant intraparenchymal CNS metastases. A third case, described by Gentile [6], is of a male with a pigmented lesion of the right face who went on to develop a right 5th, 6th, and 7th nerve
palsy, including both motor and sensory divisions of the trigeminal nerve. CT and MRI scans did not demonstrate the neural involvement and CSF studies were normal.
H&topathology Melanomas develop largely from melanocytes in the basal layer of the epidermis, where they proliferate for a variable period, spreading laterally. The tumor eventually grows downward through the dermis, infiltrating the vascular and neural structures within the reticular dermis, and demonstrating the capacity for distant spread. Some melanomas grow downward without significant cellular atypism and show mild tissue changes. Such lesions were termed 'minimal deviation melanomas' by Reed and Leonard [15], who felt them to be a precursor lesion of NTM. In their paper, many of the original lesions were felt to be recognizable as a lentigo maligna (Hutchinson's freckle), a slowly expanding melanocytic lesion, which eventually invades to become a frank melanoma. Others, particularly Ackerman [16], have disagreed with this and feel strongly that the term 'minimal deviation melanoma' is a flawed concept that need not be invoked to describe the melanomas that lack significant cellular atypism and tissue changes, and that the term 'dysplasia' is a useless term that should be discarded. Dubow and Ackerman [17] also holds that lentigo maligna-type lesions are, from the outset, slowly growing melanomas, rather than premalignant lesions. Therefore, they regards the term, 'lentigo maligna' as inappropriate and use the term melanoma in situ. In NTM, melanocytes with a spindle cell morphology often cease melanogenesis, develop neuroid properties, such as fasicle formation or neurotropism, and invade cutaneous nerves in preference to vascular spread. Because of their spindle cell morphology and neuroid features, they are initially confused with benign lesions, are later thought to be spindle cell squamous carcinomas or malignant fibrous histiocytomas, and are eventually recognized as NTM. The usual clinical evolution of a NTM consists of
170
Fig. 3. C u t a n e o u s nerves in various stages of replacement by tumor cells. (a) Two nerves in the subcutaneous fat. Note the early invasion of the right side of the lower nerve. (b) More extensive replacement of a nerve by t u m o r cells which compress the few remaining normal cells. (c) Massive replacement of a larger nerve by tumor. Note that t u m o r cells are contained within the connective tissue sheath and preserve the architecture of the surrounding tissue.
a melanocytic lesion, which is treated but recurs as one or more flesh-colored papules or nodules. Microscopically, the tumor exhibits fascicles of spindle cells with pale cytoplasms and oval nuclei. Initially, the tumor cells tend to show minimal atypism, although there is some variation in the size and shape of nuclei. The fascicles invade the dermis and are encased by sheaths that resemble a perineurium. These fasicles can be shown to blend with the perineurium of cutaneous nerves and one can often demonstrate atypical cells infiltrating the endoneurial space and, eventually, entirely replacing the nerve while maintaining the overall neuronal architecture, without involvment of adjacent tissue (Fig. 3). One sees broadened hypercellular nerves consisting of tumor cells intermixed with normal Schwann cells. Reed and Leonard [4], feel that the neuroid properties of NTM are indicative of a Schwann cell differentiation of the melanocytes, which, having lost their melanogenic role, instead begin to grow in fasicular formation and to invade nerves, based on their common neural crest origin with Schwann cells [18]. The morphologic interpretation of Schwann cell features has been supported by ultrastructural studies of neurotropic melanomas by two separate groups [9, 12]. DiMaio [12] described long cell processes arranged in bundles and closely apposed cell membranes with infoldings suggestive of Schwann cell neoplasms. Warner [9] described concentric laminations surrounding membrane bound cytoplasm that were interpreted as attempts at myelin formation. Due to the lack of melanogenesis and the often benign or low grade appearance of the lesion, diagnosis of NTM can often be difficult, especially early in the evolution of the tumor. Early NTM's are frequently misread as a neurofibroma, a bleu nevus or even as reactive fibroplasia [19]. Later, recurrences are difficult to differentiate from a spindle cell squamous carcinoma or a malignant fibrous histiocytoma, as seen in the case presented. Immunohistochemical stains have been shown to be useful in differentiating some of these entities [5, 11]. The S-100 protein, originally described in astrocytes and oligodendrocytes, has also been shown to be present in Schwann cells, melanocytes and even Langerhans cells [5, 10]. Therefore, NTM and the
171 full s p e c t r u m o f m e l a n o c y t i c n e o p l a s m s f r o m c o m m o n nevi to m a l i g n a n t m e l a n o m a s stain for S-IO0, b u t s p i n d l e cell t u m o r s of c a r c i n o m a t o u s o r fibroblastic origin, which a r e so difficult to d i f f e r e n t i a t e f r o m N T M , d o n o t so stain. It has also b e e n p r o p o s e d that S-IO0 staining m a y b e h e l p f u l in d e t e r m i n i n g w h e t h e r surgical tissue m a r g i n s a r e a d e quate.
3.
4.
5.
6.
Treatment and prognosis 7. T o d a t e , t r e a t m e n t has b e e n p r i m a r i l y surgical, b u t d i s e a s e c o n t r o l has b e e n p o o r d u e to t h e t e n d e n c y o f t h e t u m o r to h a v e infiltrating m a r g i n s a n d to i n v a d e a l o n g n e r v e s . R a d i a t i o n t h e r a p y has b e e n u s e d as an a d j u n c t [6], b u t no c l e a r b e n e f i t has b e e n d e m o n s t r a t e d . C h e m o t h e r a p y has also b e e n att e m p t e d , i n c l u d i n g i n t r a - a r t e r i a l cisplatin [6] a n d d o x o r u b i c i n [9], b u t d a t a a r e insufficient for extrap o l a t i o n , O u t c o m e is difficult to assess d u e to a p a u c i t y o f cases a n d i n c o m p l e t e f o l l o w - u p , b u t app r o x i m a t e l y 3 0 % o f p a t i e n t s h a d d i e d with active d i s e a s e , 30% w e r e alive with active d i s e a s e , a n d 40% a p p e a r e d free o f d i s e a s e , at the t i m e t h e cases w e r e p u b l i s h e d . P e r h a p s , use o f S-100 staining of surgical s p e c i m e n s to d e t e r m i n e m a r g i n s will l e a d to m o r e c o m p l e t e r e s e c t i o n s a n d b e t t e r survival.
8. 9.
10.
11.
12.
13.
14.
Acknowledgements
15.
T h e a u t h o r s wish to t h a n k D r . H e r b e r t O e t t g e n for p r o v i d i n g t h e clinical m a t e r i a l a n d r a d i o g r a p h s , D r . J a m e s W o o d r u f f for p r o v i d i n g p h o t o m i c r o g r a p h s o f t h e case r e p o r t e d , a n d Dr. J e r o m e Posner for r e v i e w i n g t h e m a n u s c r i p t a n d m a k i n g m a n y helpful suggestions.
16.
References
19.
1. Ballantyne A J, McCarten AB, Ibanez MJ: The extension of cancer of the head and neck through peripheral nerves. Am J Surg 106: 651-666, 1963 2. Clouston PD, Sharpe DM~ Corben A J, Kos S, Kennedy PJ: Perineural spread of cutaneous head and neck cancer: its
17.
18.
orbital and central neurologic complications. Arch Neurol 47: 73-77, 1990 Ackerman AB, Godomski J: Neurotropic malignant melanoma and other neurotropic neoplasms in the skin. Am J Dermatopathol 6 (Suppl 1): 63-80, 1984 Reed RJ, Leonard DD: Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg Pathol 3: 301-311, 1979 Kossard S, Doherty E, Murray E: Neurotropic melanoma: a variant of desmoplastic melanoma. Arch Dermatol 123: 907-912, 1987 Gentile RD, Donovan DT: Neurotropic melanoma of the head and neck. Laryngoscope 95: 1161-1166, 1985 Warner TF, Lloyd RV, Hafez GR, Angevine JM: Immunocytocbemistry of neurotropic melanoma. Cancer 53: 254257, 1984 Warner TF, Hafez GR, Buchler DA: Neurotropic melanoma of the vulva. Cancer 49: 999-1004, 1982 Warner TF, Hafez GR, Finch RE, Brandenberg JH: Schwann cell features in neurotropic melanoma. J Cutan Pathol 8: 177-187, 1981 Warner TF, Ford CN, Hafez GR: Neurotropic melanoma of the face invading the maxillary nerve. J Cutan Patho112: 520-527, 1985 Khalil MK, Duguid WP: Neurotropic malignant melanoma of right temple with orbital metastasis: a clinicopathological case report. Brit J Ophthalmol 71: 41-46, 1987 DiMaio SM, Mackay B, Smith JL, Dickersin GR: Neurosarcomatous transformation in malignant melanoma: an ultrastructural study. Cancer 50: 2345-2354, 1982 Woodruff WW, Yeates AE, McLendon RE: Perineural tumor extension to the cavernous sinus from superficial facial carcinoma: CT manifestations. Radiol 161: 395-399, 1986 McGinnis JP, Greet JL, Wolfe NL: Neu~otropic melanoma of the lower lip. J Oral Pathol 15: 445-449, 1986 Reed RJ: A classification of melanocytic dysplasias and malignant melanomas. Am J Dermatopathol 6 (Suppl 1): 195-206, 1984 Ackerman AB: What Naevus is dysplastic, a syndrome and the commonest precursor of malignant melanoma? A riddle and an answer. Histopathology 13: 241-256, 1988 Dubow BE, Ackerman AB: Malignant Melanoma in Situ: the evolution of a concept. Modern Pathology 13: 734-744, 1990 Weston JA: The migration and differentiation of neural crest cells. Advances in Morphogenesis 8: 41-114, 1971 Kibbi A, Mihm MC: Malignant melanoma with desmoplasia and neurotropism. J Dermatol Surg Oncol 13: 12041208, 1987
Address for offprints: E.E. Mack, Department of Neurosurgery, Division of Neurooncology, University of California at San Francisco, ACC Building, Rm A841, San Francisco, CA 94143-0372, USA
